Safety fears over laughing gas

14:46 12 August 2007

IF YOU have major surgery, there is a good chance you'll be kept unconscious using nitrous oxide or laughing gas. This anaesthetic has been around for over a century, and despite some evidence that it can cause post-operative nausea and vomiting, it is generally considered to be one of the safest going.

Now that assumption has been challenged by one of the largest clinical trials ever conducted in anaesthesiology. Paul Myles of The Alfred Hospital in Melbourne, Australia, and his colleagues found that there would be fewer potentially life-threatening complications such as wound infections and pneumonia following major surgery if nitrous oxide were replaced with oxygen in the mix of inhaled gases and alternative anaesthetics used instead (Anesthesiology, vol 107, p 221). Removing nitrous oxide may also lead to fewer heart attacks after surgery.

However, anaesthetists emphasise that nitrous oxide remains appropriate where exposure to the gas is minimal and patients are basically healthy, such as during the majority of operations on children, women in labour, and for very minor surgery.

Nitrous oxide is used routinely in major surgery, and although there is little national monitoring of anaesthetic practices, each year between 5 to 10 million patients are estimated to receive it in the US alone.

In the ENIGMA trial, 2000 patients undergoing major surgery in hospitals across the UK, Australia, and Asia received anaesthetic either with or without nitrous oxide, although the exact mix of anaesthetic was left up to the anaesthetist.

Patients in the nitrous-oxide-free group received around 80 per cent oxygen and 20 per cent nitrogen through a breathing tube, plus an anaesthetic such as propofol, which is injected into the bloodstream, or isoflurane, which is added to the gas mix at the rate of about 1 to 2 per cent.

The patients in the nitrous oxide group received around 70 per cent nitrous oxide as their baseline anaesthetic and 30 per cent oxygen, as well as other anaesthetics to put them under at the start of the operation and help keep them unconscious.

It turned out that the patients who'd had no nitrous oxide suffered half as many episodes of severe nausea and vomiting as those whose anaesthetic included the gas. They also had a 50 per cent reduction in the incidence of pneumonia, and a 20 to 30 per cent reduction in fever and wound infections.

"The evidence is sufficiently compelling to convince me to change my practice," says Alan Merry of the University of Auckland, who chairs the quality and safety committee of the Australian and New Zealand College of Anaesthetists. "I would think very carefully before using nitrous oxide in patients [undergoing major surgery]."

Myles says nitrous oxide's side effects are probably due to its well-known ability to interfere with the metabolism of vitamin B12 and folic acid, and with DNA synthesis - important for wound healing and the immune system.

Meanwhile, Daniel Sessler, an anaesthesiologist at the Cleveland Clinic in Ohio suggests that removing nitrous oxide from the gas mix is beneficial because the patient can receive more oxygen, which could directly reduce the risk of wound infection.

A larger 7000-patient trial called ENIGMA-II now hopes to address the question of whether nitrous oxide alone is responsible for more wound infections and whether it really does damage the heart. Patients receiving nitrous oxide in the ENIGMA trial had double the rate of heart attacks and three times the death rate, although the trial was not large enough to say whether that difference is significant.

ENIGMA also doesn't tell us much about any side effects possibly associated with the 20 or so other combinations of anaesthetics that might be chosen to replace nitrous oxide - most of which have never been tested in large clinical trials.

Because of the cost and logistical problems associated with such large clinical trials, "there's a huge amount known about anaesthetics in animals, and very little known in humans", says Sessler. For instance, animal studies suggest that isoflurane or propofol can encourage the protein build-up in the brain that leads to Alzheimer's disease and other memory problems, but human trials have not yet confirmed such a link.

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